Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart - PubMed (original) (raw)

Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart

B Campbell et al. J Mol Cell Cardiol. 1999 Feb.

Abstract

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. The proteasome inhibitor, PS-519, has been shown to attenuate leukocyte-endothelial cell interactions. We tested the effects of PS-519 on neutrophil mediated cardiac dysfunction in ischemia/reperfusion. This study examines the effects of PS-519 in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of PS-519 (0.01, 0.1, 0.3, 1.0 mg/kg) to I/R hearts perfused with PMNs improved coronary flow, and preserved left ventricular developed pressure (LVDP) and + dP/dt max as indices of cardiac contractile function. At 1.0 mg/kg, PS-519 treated hearts exhibited a final LVDP of 98 +/- 3% of initial compared to 52 +/- 8% in I/R hearts receiving only vehicle (P < 0.001). In addition, PS-519 significantly reduced PMN accumulation in the ischemic myocardium from 25.1 +/- 2.1 PMNs/mm2 in untreated hearts to 7.3 PMNs/mm2, and attenuated P-selectin surface expression on coronary vascular endothelium from 7.1 +/- 0.3% to 1.4 +/- 0.2% (P < 0.01). These results provide evidence that PS-519 is a potent and effective cardioprotective agent that inhibits P-selectin leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion.

PubMed Disclaimer

Cited by

Activation of Chymotrypsin-Like Activity of the Proteasome during Ischemia Induces Myocardial Dysfunction and Death.
Sanchez G, Berrios D, Olmedo I, Pezoa J, Riquelme JA, Montecinos L, Pedrozo Z, Donoso P. Sanchez G, et al. PLoS One. 2016 Aug 16;11(8):e0161068. doi: 10.1371/journal.pone.0161068. eCollection 2016. PLoS One. 2016. PMID: 27529620 Free PMC article.
Genetically induced moderate inhibition of the proteasome in cardiomyocytes exacerbates myocardial ischemia-reperfusion injury in mice.
Tian Z, Zheng H, Li J, Li Y, Su H, Wang X. Tian Z, et al. Circ Res. 2012 Aug 17;111(5):532-42. doi: 10.1161/CIRCRESAHA.112.270983. Epub 2012 Jun 26. Circ Res. 2012. PMID: 22740087 Free PMC article.
Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation.
Hasselgren PO, Fischer JE. Hasselgren PO, et al. Ann Surg. 2001 Jan;233(1):9-17. doi: 10.1097/00000658-200101000-00003. Ann Surg. 2001. PMID: 11141219 Free PMC article. Review.
Myocardial Protection and Current Cancer Therapy: Two Opposite Targets with Inevitable Cost.
Efentakis P, Andreadou I, Iliodromitis KE, Triposkiadis F, Ferdinandy P, Schulz R, Iliodromitis EK. Efentakis P, et al. Int J Mol Sci. 2022 Nov 15;23(22):14121. doi: 10.3390/ijms232214121. Int J Mol Sci. 2022. PMID: 36430599 Free PMC article. Review.
Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy.
Luo H, Wong J, Wong B. Luo H, et al. Cardiovasc Res. 2010 Jan 15;85(2):347-56. doi: 10.1093/cvr/cvp225. Epub 2009 Jul 3. Cardiovasc Res. 2010. PMID: 19578074 Free PMC article. Review.

Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart - PubMed (original) (raw)